Sodium-glucose cotransporter 2 inhibitors in transthyretin amyloid cardiomyopathy: navigating potential benefits and uncertainties

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have garnered attention for their potential role in managing transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive condition characterized by significant morbidity and mortality. ATTR-CM remains underdiagnosed despite advances in diagnostic modalities. While tafamidis and acoramidis have emerged as effective therapies, residual cardiovascular risk persists, highlighting the need for adjunctive treatments. SGLT2i, initially developed as antidiabetic agents, have demonstrated cardioprotective effects in various heart failure phenotypes, including preserved and reduced ejection fractions. Emerging evidence suggests their utility in ATTR-CM, potentially addressing unmet needs, such as symptom burden, hospitalizations, and survival. Clinical studies indicate that SGLT2i reduce all-cause mortality, major adverse cardiac events (MACE), and heart failure hospitalizations, with benefits extending to cardiovascular mortality and improved functional status. Moreover, these agents appear to mitigate arrhythmic complications, evidenced by reduced cardioversion procedures and antiarrhythmic therapy requirements. Observational studies also highlight the potential synergy of SGLT2i with tafamidis, suggesting additive benefits in addressing amyloid deposition and heart failure. However, limitations, including the absence of randomized controlled trials, immortal time bias, and population heterogeneity, necessitate further research. Future directions involve elucidating mechanisms of action, exploring personalized treatment strategies, and leveraging big data analytics for real-world insights. SGLT2i's potential to transform ATTR-CM management underscores their promise, though robust trials are imperative to validate findings and optimize clinical applications.